Sepsis is a major health issues for public and for veterans. A recent study conducted in 118 VA hospitals showed that 4.1% of patients undergoing surgery developed postoperative sepsis. The mortality rate of sepsis is high, exceeding 30%, due to a lack of efficient therapy. A great barrier for sepsis therapy is that sepsis is a multi-factor disease, involving endotoxin from bacteria, dysregulated response in immune effector cells, all of which lead to cell damage and endothelial dysfunction, resulting in organ injuries and septic death, which may explain why extensive efforts (more than 100 clinical trials) to block one or another component of the inflammatory or coagulation pathways have had little impact on patient survival. Here, we propose that targeting an endogenous factor with multi-protective effects against sepsis may present a novel approach for sepsis therapy and high density lipoprotein (HDL) is such a target. HDL is a major component of circulating blood with multi-protective properties in vascular endothelial cells and immune effector cells. However, the levels of HDL decrease by 40- 70% in septic patients, which is associated with a poor prognosis. Using mice deficient in HDL, we recently reported that mice lacking HDL are susceptible to cecal ligation and puncture (CLP)-induced septic death, and increase HDL levels protects CLP-induced septic death. These clinical and animal studies indicate that a decrease in HDL levels is a risk factor for sepsis and raising circulating HDL levels may provide an efficient therapy for sepsis. Reconstituted or synthetic HDL (sHDL) is a new tool for promoting the biological activity of HDL. In the preliminary study, we generated a new type of sHDL (YGZL3) and showed that the YGZL3 treatment significantly increases HDL levels and protects mice from CLP- and bacterial-induced septic death, indicating that sHDL (YGZL3) is a potential effective therapy for sepsis. Based on our preliminary data and existing knowledge of HDL biology, we hypothesize that sHDL therapy protects sepsis by restoring both HDL level and its multi-protective functions. The objectives of this grant are to understand the mechanism(s) underlying sHDL (YGZL3) protection against sepsis, to optimize the treatment regimen and to assess pharmacokinetics and toxicity of sHDL (YGZL3). Completion of this study will provide a body of mechanistic and preclinical data for a novel sHDL-based therapy for sepsis and position it for future Investigational New Drug (IND) studies and rapid clinical translation, which will improve the health of public and veterans.